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1.  Modeling inflammation and oxidative stress in gastrointestinal disease development using novel organotypic culture systems 
Stem Cell Research & Therapy  2013;4(Suppl 1):S5.
Gastroesophageal reflux disease (GERD), Barrett's esophagus (BE), graft-versus-host disease (GVHD), and inflammatory bowel diseases such as ulcerative colitis and Crohn's disease are common human gastrointestinal diseases that share inflammation as a key driver for their development. A general outcome resulting from these chronic inflammatory conditions is increased oxidative stress. Oxidative stress is caused by the generation of reactive oxygen and nitrogen species that are part of the normal inflammatory response, but are also capable of damaging cellular DNA, protein, and organelles. Damage to DNA can include DNA strand breaks, point mutations due to DNA adducts, as well as alterations in methylation patterns leading to activation of oncogenes or inactivation of tumor suppressors. There are a number of significant long-term consequences associated with chronic oxidative stress, most notably cancer. Infiltrating immune cells and stromal components of tissue including fibroblasts contribute to dynamic changes occurring in tissue related to disease development. Immune cells can potentiate oxidative stress, and fibroblasts have the capacity to contribute to advanced growth and proliferation of the epithelium and any resultant cancers. Disease models for GERD, BE, GVHD, and ulcerative colitis based on three-dimensional human cell and tissue culture systems that recapitulate in vivo growth and differentiation in inflammatory-associated microphysiological environments would enhance our understanding of disease progression and improve our ability to test for disease-prevention strategies. The development of physiologically relevant, human cell-based culture systems is therefore a major focus of our research. These novel models will be of enormous value, allowing us to test hypotheses and advance our understanding of these disorders, and will have a translational impact allowing us to more rapidly develop therapeutic and chemopreventive agents. In summary, this work to develop advanced human cell-based models of inflammatory conditions will greatly improve our ability to study, prevent, and treat GERD, BE, GVHD, and inflammatory bowel disease. The work will also foster the development of novel therapeutic and preventive strategies that will improve patient care for these important clinical conditions.
doi:10.1186/scrt366
PMCID: PMC3983655  PMID: 24564965
inflammation; oxidative stress; DNA damage; gastrointestinal disease; gastroesophageal reflux disease; Barrett's esophagus; graft-versus-host disease; inflammatory bowel disease; human three-dimensional organotypic model systems
2.  Concerns of and coping strategies by parents of pediatric liver transplant recipients: a qualitative study from China 
Parents of liver transplant recipient children have to face complicated health issues of their children. Coping strategies of parents as major care providers not only impacts on their handling of stresses on themselves but also on the recipients’ quality of life. In this study, we sought to investigate the coping strategies of parents of Chinese pediatric liver transplant recipients at a single tertiary care institution in China. Twenty-five parents of liver transplant recipients were selected by the purposive sampling method and data was collected using qualitative semi-structured interview. Interviews were conducted until thematic saturation was achieved. We extracted 5 major themes: 1) guilt and self-blame for not giving a happy life to the sick child; 2) seeking social support for helping to treat the sick child; 3) standing firm by not giving up on treating the sick child; 4) cautious caretaking; 5) compromise: a helpless acceptance of truth. In summary, parents of transplant recipients present 5 major coping strategies. Proper assessment of stresses on parents of liver transplant recipient children and their coping strategies may help the medical staff and social services to provide more targeted support, and help and promote the balance of the family function.
PMCID: PMC4307545  PMID: 25664098
Liver transplant; children; parents; coping; qualitative study
3.  Role of apoptosis in colon cancer biology, therapy, and prevention 
Current colorectal cancer reports  2013;9(4):10.1007/s11888-013-0188-z.
Deregulation of apoptosis is a hallmark of human cancer and contributes to therapeutic resistance. Recent advances in cancer genomics reveal a myriad of alterations in key pathways that directly or indirectly increase tumor cell survival. This review will outline the pathways of apoptosis in mammalian cells, and highlight the common alterations of apoptosis regulators found in colon cancer, the role of apoptosis and underlying mechanisms in colon cancer treatment and prevention, including recent advances on investigational agents, such as kinase inhibitors, proteasome inhibitors, HSP90 inhibitors, BH3 mimetics, TRAIL, and IAP antagonists. Topics will also include novel concepts, as well as opportunities and challenges for drug discovery and combination therapy by exploring cancer-specific genetic defects, and therefore selective induction of apoptosis in cancer cells. Although the emphasis is on colon cancer, the main theme and many of the aspects are applicable to other solid tumors.
doi:10.1007/s11888-013-0188-z
PMCID: PMC3836193  PMID: 24273467
apoptosis; colon cancer; Bcl-2 family; BH3-only protein; mitochondria; death receptor; TRAIL; EGFR; K-RAS; b-Raf; c-Myc; PI3K; IAPs; targeted therapies; sorafenib; regorafinib; vemurafenib; protesome inhibitors; Hsp90 inhibitors; autophagy; necrosis; BH3 mimetics; SMAC mimetics; NSAIDs; synthetic lethality
4.  MicroRNA-638 inhibits cell proliferation, invasion and regulates cell cycle by targeting tetraspanin 1 in human colorectal carcinoma 
Oncotarget  2014;5(23):12083-12096.
The expression of miR-638 was found downregulated in colorectal carcinoma (CRC) in our previous study. However, the role of miR-638 in CRC remains unknown. The aim of this study was to determine the function and mechanism of miR-638 in CRC. Here, we verified that miR-638 was frequently downregulated in CRC tissues compared with corresponding noncancerous tissues (NCTs) in an expanded CRC cohort, and survival analysis showed that the downregulation of miR-638 in CRC was associated with poor prognoses. The ectopic expression of miR-638 inhibited CRC cell proliferation, invasion and arrest the cell cycle in G1 phase, whereas the repression of miR-638 significantly promoted CRC cell growth, invasion and cell cycle G1/S transition. Subsequent mechanism analyses revealed that miR-638 inhibited CRC cell growth, invasion and cell cycle progression by targeting TSPAN1. TSPAN1 protein levels were upregulated in CRC samples and were inversely correlated with miR-638 levels. More importantly, high TSPAN1 expression levels in CRC tissues predicted poor overall survival, and appears to be an independent prognostic factor for CRC survival. Furthermore, CpG island methylation analyses revealed that the miR-638 promoter was hypermethylated in CRC and that attenuating promoter methylation was sufficient to restore miR-638 expression in CRC cells. Taken together, our current data demonstrate that miR-638 functions as a tumor suppressor in human CRC by inhibiting TSPAN1, and that TSPAN1 is a potential prognostic factor for CRC.
PMCID: PMC4322991  PMID: 25301729
microRNA-638; TSPAN1; cell proliferation; colorectal carcinoma; cell cycle
5.  A huge adenosquamous carcinoma of the pancreas with sarcomatoid change: An unusual case report 
World Journal of Gastroenterology : WJG  2014;20(43):16381-16386.
Adenosquamous carcinoma rarely occurs in the pancreas, and is characterized by the presence of cellular components from both duct adenocarcinoma and squamous carcinoma. Here, we describe a rare case of pancreatic adenosquamous carcinoma with sarcomatous change. Immunohistochemistry showed that the sarcomatous lesion lost the epithelial marker and aberrantly expressed of acquired mesenchymal markers, which indicated that this special histological phenotype may be attributed to epithelial-mesenchymal transition. This case also indicated that a routine radical surgery without aggressive treatment strategies was still appropriate for adenosquamous carcinoma of the pancreas with sarcomatoid change.
doi:10.3748/wjg.v20.i43.16381
PMCID: PMC4239535  PMID: 25473201
Adenosquamous carcinoma; Sarcomatoid change; Pancreatic tumors; Histopathological types; Epithelial-mesenchymal transition
6.  Hsp90 inhibitors promote p53-dependent apoptosis through PUMA and Bax 
Molecular cancer therapeutics  2013;12(11):10.1158/1535-7163.MCT-13-0284.
Heat shock protein 90 (Hsp90) is widely overexpressed in cancer cells and believed to be essential for the maintenance of malignant phenotypes. Targeting Hsp90 by small molecules has shown promises in solid and hematological malignancies, which likely involves degradation of client oncoproteins in a cell-type specific manner. In this study, we found that structurally unrelated Hsp90 inhibitors induce DNA damage and apoptosis via p53-dependent induction of PUMA, which indirectly triggers Bax activation and mitochondrial dysfunction in colon cancer cells. Deficiency in PUMA, BAX, or p53 at lesser extent, abrogated 17AAG-induced apoptosis and mitochondrial dysfunction, and enhanced clonogenic cell survival. Furthermore, suppression of p53-dependent p21 induction or enhanced p53 activation synergized with 17AAG to induce PUMA-dependent apoptosis. Finally, PUMA was found to mediate apoptotic and therapeutic responses to the 17AAG analog 17DMAG in xenografts. These results demonstrate an important role of the p53/PUMA/Bax axis in Hsp90 inhibitor-induced killing of p53 WT cells, and have important implications for their clinical applications.
doi:10.1158/1535-7163.MCT-13-0284
PMCID: PMC3823684  PMID: 23966620
Hsp90 inhibitors; PUMA; p53; apoptosis; colon cancer
7.  Crystal structure of di­chlorido­(2,2′:6′,2′′-terpyridine-κ3 N,N′,N′′)zinc: a redeter­min­ation 
The crystal structure of the title compound, [ZnCl2(C15H11N3)], was redetermined based on modern CCD data. In comparison with the previous determination from photographic film data [Corbridge & Cox (1956 ▶). J. Chem. Soc. 159, 594–603; Einstein & Penfold (1966 ▶). Acta Cryst. 20, 924–926], all non-H atoms were refined with anisotropic displacement parameters, leading to a much higher precision in terms of bond lengths and angles [e.g. Zn—Cl = 2.2684 (8) and 2.2883 (11) compared to 2.25 (1) and 2.27 (1) Å]. In the title mol­ecule, the ZnII atom is five-coordinated in a distorted square-pyramidal mode by two Cl atoms and by the three N atoms from the 2,2′:6′,2′′-terpyridine ligand. The latter is not planar and shows dihedral angles between the least-squares planes of the central pyridine ring and the terminal rings of 3.18 (8) and 6.36 (9)°. The mol­ecules in the crystal structure pack with π–π inter­actions [centroid–centroid distance = 3.655 (2) Å] between pyridine rings of neighbouring terpyridine moieties. These, together with inter­molecular C—H⋯Cl inter­actions, stablize the three-dimensional structure.
doi:10.1107/S1600536814023605
PMCID: PMC4257341  PMID: 25484786
crystal structure; redetermination; 2,2′:6′,2′′-terpyridine; zinc complex; π–π inter­actions
8.  Effectiveness and Safety of Chemotherapy Combined with Dendritic Cells Co-Cultured with Cytokine-Induced Killer Cells in the Treatment of Advanced Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(9):e108958.
Background
Lung cancer, particularly non-small-cell lung cancer (NSCLC) is the leading cause of cancer mortality. Chemotherapy combined dendritic cells co-cultured with cytokine-induced killer cells (DC-CIK) immunotherapy has been applied in advanced NSCLC patients' treatment, but couldn't provide consistent beneficial results. Therefore, it is necessary to evaluate the efficiency and safety of combination therapy to promote the application.
Methods
A literature search for randomized controlled trials of NSCLC was conducted in PubMed database. Before meta-analysis was performed, studies were evaluated heterogeneity. Pooled risk ratios (RRs) were estimated and 95% confidence intervals (CIs) were calculated using a fixed-effect model. Sensitivity analysis was also performed.
Results
Six eligible trials were enrolled. Efficiency and safety of chemotherapy followed by DC-CIK immunotherapy (experimental group) and chemotherapy alone (control group) were compared. 1-year overall survival (OS) (P = 0.02) and progression free survival (PFS) (P = 0.005) in the experimental group were significantly increased compared with the control. Disease control rate (DCR) (P = 0.006) rose significantly in experimental group. However, no significant differences between the two groups were observed in 2-year OS (P = 0.21), 2-year PFS (P = 0.10), overall response rate (ORR) (P = 0.76) and partial response (PR) (P = 0.22). Temporary fever, anemia, leukopenia and nausea were the four major adverse events (AEs) treated by chemotherapy. The incidence of anemia, leukopenia and nausea in the experimental group was obviously lower than the control group. Temporary fever rate was higher in experimental group than that in the control, but could be alleviated by taking sufficient rest.
Conclusions
Chemotherapy combined with DC-CIK immunotherapy showed superiority in DCR, 1-year OS and PFS, and no more AEs appeared, however, there was no significant improvement in ORR, PR, 2-year OS and PFS. As a whole, the combination therapy is safer but modest in efficacy for advanced NSCLC patients.
doi:10.1371/journal.pone.0108958
PMCID: PMC4182599  PMID: 25268709
9.  High-frequency aberrantly methylated targets in pancreatic adenocarcinoma identified via global DNA methylation analysis using methylCap-seq 
Clinical Epigenetics  2014;6(1):18.
Background
Extensive reprogramming and dysregulation of DNA methylation is an important characteristic of pancreatic cancer (PC). Our study aimed to characterize the genomic methylation patterns in various genomic contexts of PC. The methyl capture sequencing (methylCap-seq) method was used to map differently methylated regions (DMRs) in pooled samples from ten PC tissues and ten adjacent non-tumor (PN) tissues. A selection of DMRs was validated in an independent set of PC and PN samples using methylation-specific PCR (MSP), bisulfite sequencing PCR (BSP), and methylation sensitive restriction enzyme-based qPCR (MSRE-qPCR). The mRNA and expressed sequence tag (EST) expression of the corresponding genes was investigated using RT-qPCR.
Results
A total of 1,131 PC-specific and 727 PN-specific hypermethylated DMRs were identified in association with CpG islands (CGIs), including gene-associated CGIs and orphan CGIs; 2,955 PC-specific and 2,386 PN-specific hypermethylated DMRs were associated with gene promoters, including promoters containing or lacking CGIs. Moreover, 1,744 PC-specific and 1,488 PN-specific hypermethylated DMRs were found to be associated with CGIs or CGI shores. These results suggested that aberrant hypermethylation in PC typically occurs in regions surrounding the transcription start site (TSS). The BSP, MSP, MSRE-qPCR, and RT-qPCR data indicated that the aberrant DNA methylation in PC tissue and in PC cell lines was associated with gene (or corresponding EST) expression.
Conclusions
Our study characterized the genome-wide DNA methylation patterns in PC and identified DMRs that were distributed among various genomic contexts that might influence the expression of corresponding genes or transcripts to promote PC. These DMRs might serve as diagnostic biomarkers or therapeutic targets for PC.
doi:10.1186/1868-7083-6-18
PMCID: PMC4177372  PMID: 25276247
CGI shore; DNA methylation; genome-wide; methyl capture sequencing; orphan CGI; pancreatic adenocarcinoma
10.  Management of bile duct injuries combined with accessory hepatic duct during laparoscopic cholecystectomy 
World Journal of Gastroenterology : WJG  2014;20(34):12363-12366.
Bile duct injuries (BDIs) are difficult to avoid absolutely when the biliary tract has a malformation, such as accessory hepatic duct. Here, we investigated the management strategies for BDI combined with accessory hepatic duct during laparoscopic cholecystectomy.
doi:10.3748/wjg.v20.i34.12363
PMCID: PMC4161826  PMID: 25232275
Bile duct injuries; Accessory hepatic duct; Laparoscopic cholecystectomy; Management strategies; Hepatoenterostomy
11.  Comparison of Abbott and Da-an real-time PCR for quantitating serum HBV DNA 
World Journal of Gastroenterology : WJG  2014;20(33):11762-11769.
AIM: To compare the performance of the Da-an real-time hepatitis B virus (HBV) DNA assay and Abbott RealTime HBV assay.
METHODS: HBV DNA standards as well as a total of 180 clinical serum samples from patients with chronic hepatitis B were measured using the Abbott and Da-an real-time polymerase chain reaction (PCR) assays. Correlation and Bland-Altman plot analysis was used to compare the performance of the Abbott and Da-an assays. The HBV DNA levels were logarithmically transformed for analysis. All statistical analyses were performed using SPSS for Windows version 18.0. The correlation between the two assays was analyzed by Pearson’s correlation and linear regression. The Bland-Altman plots were used for the analysis of agreement between the two assays. A P value of < 0.05 was considered statistically significant.
RESULTS: The HBV DNA values measured by the Abbott or Da-an assay were significantly correlated with the expected values of HBV DNA standards (r = 0.999, for Abbott; r = 0.987, for Da-an, P < 0.001). A Bland-Altman plot showed good agreement between these two assays in detecting HBV DNA standards. Among the 180 clinical serum samples, 126 were quantifiable by both assays. Fifty-two samples were detectable by the Abbott assay but below the detection limit of the Da-an assay. Moreover, HBV DNA levels measured by the Abbott assay were significantly higher than those of the Da-an assay (6.23 ± 1.76 log IU/mL vs 5.46 ± 1.55 log IU/mL, P < 0.001). A positive correlation was observed between HBV DNA concentrations determined by the two assays in 126 paired samples (r = 0.648, P < 0.001). One hundred and fifteen of 126 (91.3%) specimens tested with both assays were within mean difference ± 1.96 SD of HBV DNA levels.
CONCLUSION: The Da-an assay presented lower sensitivity and a narrower linear range as compared to the Abbott assay, suggesting the need to be improved.
doi:10.3748/wjg.v20.i33.11762
PMCID: PMC4155366  PMID: 25206280
Hepatitis B virus; Hepatitis B virus DNA quantitation; Real-time polymerase chain reaction; Chronic hepatitis B; Antiviral therapy
12.  Extranodal Extension of Metastatic Papillary Thyroid Carcinoma: Correlation with Biochemical Endpoints, Nodal Persistence, and Systemic Disease Progression 
Thyroid  2013;23(9):1099-1105.
Background
The impact of extranodal extension (ENE) of metastatic papillary thyroid carcinoma (PTC) on short- and long-term clinical outcomes, including biochemical testing, has not been reported.
Methods
This single-institution National Cancer Institute-designated Comprehensive Cancer Center cohort study included patients with macroscopic metastases and excluded patients with gross residual disease after surgery, distant disease, or poorly differentiated papillary carcinoma. A suppressed or stimulated thyroglobulin (Tg) <1 ng/mL, without suspicious imaging or anti-thyroglobulin antibodies, after radioactive iodine (RAI) treatment was termed an excellent or “complete biochemical response” (CR).
Results
Of 89 subjects included, 60 previously untreated patients underwent total thyroidectomy and therapeutic neck dissection; 29 additional patients underwent a neck dissection for persistence or recurrence after prior surgery and RAI administration. ENE, identified in 29 patients (33%), was associated with T4 classification (p=0.02) and involvement of a greater number of nodes (median 11 vs. 5, p=0.03). ENE was associated with a 20% increased risk of nodal persistence necessitating additional surgery (p=0.02). In a multivariable analysis, ENE, T4 classification, and recurrence/persistence proved to be independent predictors of systemic disease progression (ENE: hazard ratio [HR] 4.3 [95% confidence interval (CI) 1.2–15], p=0.02; T4 classification: HR 4.2 [CI 1.3–14], p=0.01; recurrent/persistent status: HR 3.6 [CI 1.1–12], p=0.035). Nodal or systemic disease progression was rare after a biochemical CR; in contrast, in previously untreated patients, stimulated Tg levels (sTg) >50 ng/mL prior to initial RAI administration, heralded the progression of nodal disease, and also predicted the eventual development of systemic disease (p=0.0001). Of those with a sTg >50 ng/mL, over 70% underwent surgery for nodal persistence within five years. The presence of ENE diminished the odds of a biochemical CR (odds ratio 3.5% [CI 1.3–10], p=0.02), and increased the probability that the sTg levels after surgery will exceed 50 ng/mL (odds ratio 5 [CI 1.2–21], p=0.03). Following surgery for tumor persistence, 25% of those with ENE were rendered biochemically free of disease.
Conclusions
ENE diminishes the probability of a biochemical CR after treatment for regional metastatic PTC, and increases the probability of tumor persistence after initial resection, likely from abundant metastasis. ENE and nodal persistence independently predict eventual systemic disease progression.
doi:10.1089/thy.2013.0027
PMCID: PMC3770240  PMID: 23421588
13.  TAp73 promotes cell survival upon genotoxic stress by inhibiting p53 activity 
Oncotarget  2014;5(18):8107-8122.
p53 plays a key role in regulating DNA damage response by suppressing cell cycle progression or inducing apoptosis depending on extent of DNA damage. However, it is not clear why mild genotoxic stress favors growth arrest, whereas excessive lesions signal cells to die. Here we showed that TAp73, a p53 homologue thought to have a similar function as p53, restrains the transcriptional activity of p53 and prevents excessive activation of its downstream targets upon low levels of DNA damage, which results in cell cycle arrest. Extensive DNA damage triggers TAp73 depletion through ubiquitin/proteasome-mediated degradation of E2F1, leading to enhanced transcriptional activation by p53 and subsequent induction of apoptosis. These findings provide novel insights into the regulation of p53 function and suggest that TAp73 keeps p53 activity in check in regulating cell fate decisions upon genotoxic stress.
PMCID: PMC4226670  PMID: 25237903
14.  Effect of ERK1/2 Signaling Pathway in Electro-Acupuncture – Mediated Up-Regulation of Heme Oxygenase-1 in Lungs of Rabbits with Endotoxic Shock 
Background
The anti-oxidative and anti-inflammatory activities of electro-acupuncture (EA), a traditional clinical method, are widely accepted, but its mechanisms are not yet well defined. In this study, we investigated the role of extracellular signal-regulated kinases1/2 (ERK1/2) pathways on electro-acupuncture – mediated up-regulation of heme oxygenase-1 (HO-1) in rabbit lungs injured by LPS-induced endotoxic shock.
Material/Methods
Seventy rabbits were randomly divided into 7 groups: group C, group M, group D, group SEAM, group EAM, group EAMPD, and group PD98059. Male New England white rabbits were given EA treatment on both sides once a day on days 1–5, and then received LPS to replicate the experimental model of injured lung induced by endotoxic shock. Then, they were killed by exsanguination at 6 h after LPS administration. The blood samples were collected for serum examination, and the lungs were removed for pathology examination, determination of wet-to-dry weight ratio, MDA content, SOD activity, serum tumor necrosis factor-α, determination of HO-1 protein and mRNA expression, and determination of ERK1/2 protein.
Results
The results revealed that after EA treatment, expression of HO-1and ERK1/2 was slightly increased compared to those in other groups, accompanied with less severe lung injury as indicated by lower index of lung injury score, lower wet-to-dry weight ratio, MDA content, and serum tumor necrosis factor-α levels, and greater SOD activity (p<0.05 for all). After pretreatment with ERK1/2 inhibitor PD98059, the effect of EA treatment and expression of HO-1 were suppressed (p<0.05 for all).
Conclusions
After electro-acupuncture stimulation at ST36 and BL13, severe lung injury during endotoxic shock was attenuated. The mechanism may be through up-regulation of HO-1, mediated by the signal transductions of ERK1/2 pathways. Thus, the regulation of ERK1/2 pathways via electro-acupuncture may be a therapeutic strategy for endotoxic shock.
doi:10.12659/MSM.890736
PMCID: PMC4144948  PMID: 25139460
Acupuncture; Acute Lung Injury; Mitogen-Activated Protein Kinase 1
15.  Role of Nrf2/ARE Pathway in Protective Effect of Electroacupuncture against Endotoxic Shock-Induced Acute Lung Injury in Rabbits 
PLoS ONE  2014;9(8):e104924.
NF-E2 related factor 2 (Nrf2) is a major transcription factor and acts as a key regulator of antioxidant genes to exogenous stimulations. The aim of current study was to determine whether Nrf2/ARE pathway is involved in the protective effect of electroacupuncture on the injured lung in a rabbit model of endotoxic shock. A dose of lipopolysaccharide (LPS) 5 mg/kg was administered intravenously to replicate the model of acute lung injury induced by endotoxic shock. Electroacupuncture pretreatment was handled bilaterally at Zusanli and Feishu acupoints for five consecutive days while sham electroacupuncture punctured at non-acupoints. Fourty anesthetized New England male rabbits were randomized into normal control group (group C), LPS group (group L), electroacupuncture + LPS group (group EL) and sham electroacupuncture + LPS (group SEL). At 6 h after LPS administration, the animals were sacrificed and the blood samples were collected for biochemical measurements. The lungs were removed for calculation of wet-to-dry weight ratios (W/D), histopathologic examination, determination of heme oxygenase (HO)-1 protein and mRNA, Nrf2 total and nucleoprotein, as well as Nrf2 mRNA expression, and evaluation of the intracellular distribution of Nrf2 nucleoprotein. LPS caused extensive morphologic lung damage, which was lessened by electroacupuncture treatment. Besides, lung W/D ratios were significantly decreased, the level of malondialdehyde was inhibited, plasma levels of TNF-α and interleukin-6 were decreased, while the activities of superoxide dismutase, glutathione peroxidase and catalase were enhanced in the electroacupucnture treated animals. In addition, electroacupuncture stimulation distinctly increased the expressions of HO-1 and Nrf2 protein including Nrf2 total protein and nucleoprotein as well as mRNA in lung tissue, while these effects were blunted in the sham electroacupuncture group. We concluded that electroacupuncture treatment at ST36 and BL13 effectively attenuates lung injury in a rabbit model of endotoxic shock through activation of Nrf2/ARE pathway and following up-regulation of HO-1 expression.
doi:10.1371/journal.pone.0104924
PMCID: PMC4130631  PMID: 25115759
16.  DNA methylation-mediated silencing of matricellular protein dermatopontin promotes hepatocellular carcinoma metastasis by α3β1 integrin-Rho GTPase signaling 
Oncotarget  2014;5(16):6701-6715.
Dermatopontin (DPT), a tyrosine-rich, acidic matricellular protein, has been implicated in several human cancers. However, its biological functions and molecular mechanisms in cancer progression, particular hepatocellular carcinoma (HCC), remain unknown. We demonstrated that DPT was significantly down-regulated in 202 HCC clinical samples and that its expression level was closely correlated with cancer metastasis and patient prognosis. The overexpression of DPT dramatically suppressed HCC cell migration in vitro and intrahepatic metastasis in vivo. We further revealed that the down-regulation of DPT in HCC was due to epigenetic silencing by promoter DNA methylation. And the inhibitory effects of DPT on HCC cell motility were associated with dysregulated focal adhesion assembly, decreased RhoA activity and reduced focal adhesion kinase (FAK) and c-Src tyrosine kinase (Src) phosphorylation, and all of these alterations required the involvement of integrin signaling. Furthermore, we determined that the inhibitory effects of DPT on HCC cell motility were primarily mediated through α3β1 integrin. Our study provides new evidence for epigenetic control of tumor microenvironment, and suggests matricellular protein DPT may serve as a novel prognostic marker and act as a HCC metastasis suppressor.
PMCID: PMC4196157  PMID: 25149533
Dermatopontin; Hepatocellular Carcinoma; Patient prognosis; Methylation; Metastasis; α3β1 integrin
17.  Association between Dairy Intake and Gastric Cancer: A Meta-Analysis of Observational Studies 
PLoS ONE  2014;9(7):e101728.
Purpose
Observational studies have given inconsistent findings on the relationship between intake of dairy products and gastric cancer. We therefore conducted a systematic review with a meta-analysis of observational studies to summarize available evidence on this point.
Methods
We searched the electronic literature databases of PubMed (Medline), EMBASE and the Chinese Biomedical Literature Database up until August 30, 2013. All studies were limited to the English language. Random-effects models were used to pool study results between dairy products consumption and the risk of gastric cancer. We also performed subgroup, publication bias and sensitivity analysis.
Results
Eight prospective studies and 18 case-control studies were included in our analysis, with a total number of 7272 gastric cancer cases and 223,355 controls. Pooled relative risks of all studies showed no significant association between dairy intake and gastric cancer (odds ratio [OR]: 1.09, 95% confidence interval [CI]: 0.96–1.25). When study design was separately analyzed, population-based case-control studies showed a positive association between dairy intake and gastric cancer risk (OR: 1.36; 95% CI: 1.07–1.74), whereas no associations were shown by hospital-based case-control studies (OR: 0.86, 95% CI: 0.72–1.02) or cohort studies (OR = 1.01, 95% CI = 0.91–1.13).
Conclusions
The meta-analysis shows that no clear association apparently exists between consumption of dairy products and gastric cancer risk. Further well-designed cohort and intervention studies should be conducted to verify this lack of association.
doi:10.1371/journal.pone.0101728
PMCID: PMC4090187  PMID: 25006674
18.  Ferredoxin reductase affects p53-dependent, 5-fluorouracil–induced apoptosis in colorectal cancer cells 
Nature medicine  2001;7(10):1111-1117.
Loss of p53 gene function, which occurs in most colon cancer cells, has been shown to abolish the apoptotic response to 5-fluorouracil (5-FU). To identify genes downstream of p53 that might mediate these effects, we assessed global patterns of gene expression following 5-FU treatment of isogenic cells differing only in their p53 status. The gene encoding mitochondrial ferredoxin reductase (protein, FR; gene, FDXR) was one of the few genes significantly induced by p53 after 5-FU treatment. The FR protein was localized to mitochondria and suppressed the growth of colon cancer cells when over-expressed. Targeted disruption of the FDXR gene in human colon cancer cells showed that it was essential for viability, and partial disruption of the gene resulted in decreased sensitivity to 5-FU-induced apoptosis. These data, coupled with the effects of pharmacologic inhibitors of reactive oxygen species, indicate that FR contributes to p53-mediated apoptosis through the generation of oxidative stress in mitochondria.
doi:10.1038/nm1001-1111
PMCID: PMC4086305  PMID: 11590433
19.  Epidemiological survey of human cytomegalovirus antibody levels in children from Southeastern China 
Virology Journal  2014;11:123.
Background
This study investigated infection status and distribution of human cytomegalovirus (HCMV) serum markers in hospitalized children from the Wenzhou region.
Methods
This survey was performed on 10,147 hospitalized children from birth to 14 years of age in Southeastern China (Wenzhou region) from March 2010 to March 2013. IgM and IgG antibodies to HCMV were quantitatively detected by chemiluminescence immunoassay (CLIA). HCMV IgM or IgG detection rates, concentration, and distribution in various age groups were retrospectively analyzed.
Results
In this study of hospitalized children, the overall rates of HCMV IgM+ and IgG+ were 10.8% (1,099/10,147) and 83.0% (8,425/10,147), respectively. The lowest HCMV IgM+ rate (1.0%, P < 0.001) was observed in the group of patients <28 days of age whereas the highest HCMV IgM+ rate (19.9%, P < 0.001) occurred in the 28 days ~ 5 months old group. However, the concentrations of HCMV specific IgM in all age groups were not significantly different (P > 0.05). The HCMV IgG+ rate was highest in the <28 days group (98.1%, P < 0.001). The 28 days ~ 5 months old group had the lowest HCMV specific IgG concentrations (median, 133.9 AU/mL, P < 0.001). Among 1,099 HCMV IgM+ children, 405 (36.9%) were diagnosed with respiratory infections which pneumonia accounted for 18.2% (200/1,099) of the total population. However, children with respiratory infections had the lowest HCMV IgG concentrations (median, 161.1 AU/mL, P < 0.05).
Conclusions
HCMV specific antibody responses are very common in hospitalized children with respiratory infection in Wenzhou region. Protection against HCMV airway infection needs greater emphasis and further studies will be helpful to reveal the role of HCMV in children respiratory disease.
doi:10.1186/1743-422X-11-123
PMCID: PMC4094890  PMID: 24996226
Human cytomegalovirus; Chemiluminescence immunoassay; Southeastern China; Child
20.  Novel S-Gal® analogs as 1H MRI reporters for in vivo detection of β-galactosidase 
Magnetic resonance imaging  2013;31(6):1006-1011.
The quantitative assessment of gene expression and related enzyme activity in vivo could be important for the characterization of gene altering diseases and therapy. The development of imaging techniques, based on specific reporter molecules may enable routine non-invasive assessment of enzyme activity and gene expression in vivo. We recently reported the use of commercially available S-Gal® as a β-galactosidase reporter for 1HMRI, and the synthesis of several S-Gal® analogs with enhanced response to β-galactosidase activity. We have now compared these analogs in vitro and have identified the optimal analog, C3-GD, based on strong T1 and T2 response to enzyme presence (ΔR1 and ΔR2 ∼ 1.8 times S-Gal®). Moreover, application is demonstrated in vivo in human breast tumor xenografts. MRI studies in MCF7-lacZ tumors implanted subcutaneously in athymic nude mice (n = 6), showed significant reduction in T1 and T2 values (each ∼ 13%) 2 h after intratumoral injection of C3-GD, whereas the MCF7 (wild type) tumors showed slight increase. Thus, C3-GD successfully detects β-galactosidase activity in vivo and shows promise as a lacZ gene 1HMR reporter molecule.
doi:10.1016/j.mri.2013.03.001
PMCID: PMC3800276  PMID: 23602729
β-galactosidase; 1H MRI; T1; T2; Signal enhancement; Fe-chelation; lacZ; Gene reporters
21.  2-{4-[Bis(4-bromo­phen­yl)amino]­benzyl­idene}malono­nitrile 
In the crystal structure of the title compound, C22H13Br2N3, the two bromo­phenyl rings are rotated out of the plane of the central benzyl­idene ring by 68.7 (1) and 69.3 (1)°. Both cyano substituents are located nearly in the plane of the benzylidene ring, with the mean plane of the methylmalononitrile group being inclined to this ring by 5.8 (1)°. In the crystal, the mol­ecules are linked by weak C—H⋯N hydrogen bonds into layers parallel to the bc plane.
doi:10.1107/S1600536814013816
PMCID: PMC4120592  PMID: 25161579
crystal structure
22.  A Novel p. Gly630Ser Mutation of COL2A1 in a Chinese Family with Presentations of Legg–Calvé–Perthes Disease or Avascular Necrosis of the Femoral Head 
PLoS ONE  2014;9(6):e100505.
Objective
Mutations in the type II collagen gene are associated with certain human disorders, collectively termed type II collagenopathies. They include Legg–Calvé–Perthes disease (LCPD) and avascular necrosis of the femoral head (ANFH). These two diseases are skeletal dysplasias, inherited in an autosomal dominant fashion, characterized by groin pain, dislocation of the hip and diminished joint mobility. Coxa vara and elevation of the greater trochanter of the femur comprise the typical phenotype of LCPD, but do not occur in ANFH. Lack of synthesis of type II collagen and structural defects are responsible for the major clinical outcomes, because collagen is the essential matrix protein of all connective tissues. Type II collagen, encoded by the COL2A1 gene, contains N- and C- terminal regions that are cleaved after secretion into the extracellular matrix, and the core area is composed of a triple helical (Gly–X–Y) domain. If the Gly in this specific region is replaced by other amino acids, the structure of type II collagen will be destroyed.
Method
Forty-five members of a four-generation family were recruited and investigated. Diagnosis was made by independent orthopedic surgeons and radiologists. A mutation of the COL2A1 gene was detected.
Result
In our research, we identify a heterozygous mutation (c.1888 G>A, p. Gly630Ser) in exon 29 of COL2A1 in the Gly–X–Y domain, in a Chinese family affected by LCPD and ANFH. Our findings provide significant clues to the phenotype–genotype relationships in these syndromes and may be helpful in clinical diagnosis. Furthermore, these results should assist further studies of the mechanisms underlying collagen diseases.
Conclusion
Our data add new variants to the repertoire of COL2A1 mutation resulting in related collagenopathies.
doi:10.1371/journal.pone.0100505
PMCID: PMC4065060  PMID: 24949742
23.  Effect of Nourishing “Yin”-Removing “Fire” Chinese Herbal Mixture on Hypothalamic NKB/NK3R Expression in Female Precocious Rats 
Aim. The present study aims to investigate the effects of nourishing “Yin”-removing “Fire” Chinese herb mixture on the hypothalamic NKB/NK3R expression in female precocious model rats. Materials and Methods. Female Sprague-Dawley rats were randomly divided into four groups: normal (N), central precocious puberty (CPP) model (M), CPP fed with Chinese herbal mixture (CHM), and CPP fed with normal saline (MS). Rats on postnatal day 5 were given a single subcutaneous injection of 300 μg to establish CPP model rats. Rats of CHM and MS groups were continuously administered with nourishing “Yin”-removing “Fire” Chinese herb mixture or saline since postnatal day 15. The expressions of hypothalamic NKB/NK3R were detected by means of real-time PCR, western blot, and immunofluorescence histochemistry. Results. The day of vaginal opening and establishment of two regular estrous cycles were delayed in the CHM group compared with M and MS groups. The expression of hypothalamic NKB/NK3R mRNA and protein in the arcuate nucleus (ARC) and medial preoptic (MPO) area were decreased significantly in the CHM group compared with the M and MS groups on the day of onset-puberty. Conclusions. These results indicate that the NKB/NK3R signaling pathway might be involved in the effect of herbal mixture treatment on CPP.
doi:10.1155/2014/217424
PMCID: PMC4083706  PMID: 25031603
24.  IL-22 promotes the migration and invasion of gastric cancer cells via IL-22R1/AKT/MMP-9 signaling 
IL-22, one important inflammatory cytokine of the IL-10 family, exerts its functions via IL-22 receptor that is composed of IL-22R1 and IL-10R2 subunits. Although IL-22 expression is reported to be elevated in many cancers, and increased IL-22 expression correlates with tumor progression and poor prognosis, little is known about the role of IL-22 in gastric cancer. In our study, we found that IL-22 stimulation promoted the migration and invasion of SGC-7901 cells. Furthermore, IL-22 increased AKT activation and MMP-9 production in a time- and dose-dependent manner, while knockdown of IL-22R1 attenuated the effect of IL-22 on gastric cancer cells. In addition, blocking of AKT activation suppressed the expression and secretion of MMP-9. Taken together, this present study suggests that IL-22 stimulation enhances the migration and invasion of gastric cancer cells by regulating IL-22R1/AKT/MMP-9 signaling axis.
PMCID: PMC4128980  PMID: 25120745
IL-22; migration; invasion; IL-22R1; gastric cancer; MMP-9
25.  A 41-gene signature derived from breast cancer stem cells as a predictor of survival 
Purpose
The aim of this study was to evaluate the ability of a 41-gene signature derived from breast cancer stem cells (BCSCs) to estimate the risk of metastasis and survival in breast cancer patients.
Methods
The centroid expression of the 41-gene signature derived from BCSCs was applied as the threshold to classify patients into two separate groups—patients with high expression (high-EL) of the prognostic signature and patients with low expression (low-EL). The predictive ability of the 41-gene signature was evaluated by Cox regression model and was compared against other popular tests, such as Oncotype and MammaPrint.
Results
Our results showed that the 41-gene prognostic signature was significantly associated with age (P = .0351) and ER status (P = .0095). The analysis indicated that patients in the high-EL group had a worse prognosis than those in the low-EL group in terms of both overall survival (OS: HR, 2.05, P = .009) and distant metastasis-free survival (DMFS: HR, 2.24, P = .002). Additionally, the 41-gene signature was an independent risk factor and separates patients based on estrogen receptor status. While comparable to Oncotype, the analysis demonstrated that the 41-gene signature had a better prognostic value in predicting DMFS and OS than AOL, NPI, St. Gallen, Veridex, and MammaPrint.
Conclusions
This study confirms the utility of the 41-gene signature and adds to the growing evidence that gene expression signatures of BCSCs have clinical potential to predict patient outcome and aid in treatment choice.
doi:10.1186/1756-9966-33-49
PMCID: PMC4229870  PMID: 24906694
Prognostic signature; Breast cancer; Stem cell

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